Currently, therapeutic treatment options for metastatic prostate cancer patients are exceedingly limited and consist largely of palliative care. We propose to develop radiotherapeutic peptides that have the capability of dramatically extending the residence time of the agent in prostate cancer tissue. This increase in prostate cancer residence time would be expected to substantially enhance the effectiveness, safety and potential for clinical translation of the radiotherapeutic agent. Objective: For many receptor-targeted agents for cancer, the lack of residence time at the tumor site is a major impediment to their clinical translation. With respect to radiotherapeutic applications, the short residence time limits the achievable radiotherapeutic dose for the tumor thus limiting the therapeutic benefit. Tumor hypoxia is the result of poor vascular organization leading to the impaired delivery of oxygen to portions of the tumor. Clinically, prostate cancer has been shown to be among the most hypoxic of cancers investigated. The objective of this proposal is to develop BB2r-targeted agents that utilize hypoxia-selective trapping agents and exploit the hypoxic nature of prostate cancer to increase the residence time of the agent in the tumor. We expect, and have demonstrated, that the incorporation of hypoxia-selective trapping agents (e.g., 2-nitroimidazoles) into the BB2r-targeted agent design will substantially increase the retention of diagnostic and/or radiotherapeutic agents in prostate cancer. If successful, we envision that incorporation of hypoxia- selective trapping agents would be widely applicable for a variety of receptor-avid agents and lead to an increase to the efficacy, safety and potential for clinical translation of a wide variety of diagnostic and therapeutic platforms for cancer. Specific Aims: (1) Synthesize, Characterize and Evaluate in vitro 177Lu-BB2r-Targeted Analogs Incorporating Hypoxia-Selective Trapping Agents, (2) Biodistribution, Histological and Molecular Imaging Studies of Hypoxia Enhanced 177Lu-BB2r-targeted Analogs in vivo and (3) Therapeutic Evaluation of Hypoxia Enhanced 177Lu- and 90Y-BB2r-targeted Analogs in Xenograft and Genetically Engineered Mouse Models of Prostate Cancer Study Design: The first aim of this proposal is to synthesize, characterize and evaluate the in vitro properties of hypoxia-enhanced 177Lu-BB2r-targeted agents. In vitro evaluation will include competitive receptor binding, internalization, efflux and metabolism identification of the agents under both hypoxic and normoxic conditions. Upon adequate in vitro results, the initial in vivo evaluation of the hypoxia-enhanced 177Lu-BB2r-targeted agents will be carried out in a PC-3-(HRE-Luc) xenograft mouse model. These in vivo investigations will include biodistribution, human dose estimates, histopathology and molecular imaging studies. For hypoxia- enhanced BB2r-targeted agents that are deemed to be strong candidates for therapy, these agents will undergo therapeutic investigation in PC-3-(HRE-Luc) and patient-derived xenograft models as well as genetically-engineered mouse models of prostate cancer. These therapy studies will include evaluation of 177Lu- and 90Y-BB2r targeted agents in combination with docetaxel, a common chemotherapeutic and known radiosensitizer in prostate cancer treatment. As part of the therapy studies, maximum tolerated doses will be determined and toxicities will be assessed by histopathological analysis. .